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Infected walled-off necrosis (WON) is a major complication of acute pancreatitis, and its mortality rate can reach up to 20 to 30%. Its treatment is based on a multidisciplinary approach and requires antibiotics alongside drainage, which must be as minimally invasive as possible. Studies have been carried out to identify the main bacteria responsible for these infections and to guide the antibiotic therapy. The most recent series have shown fewer infections due to gram-negative bacilli. They have also shown an increased prevalence of gram-positive infections, the emergence of multidrug resistant bacteria, and an increase in fungal infections (Candida spp.). The overuse of antibiotics for non-infected WON might be the cause of these changes. Antibiotics should be adapted to microbiological samples taken from collections as much as possible. The occurrence of WON infection is a formal indication for drainage. Therapeutic echo-endoscopy occupies a central place in the “step-up” approach, which favors the use of the least invasive techniques first. Indeed, endoscopic necrosectomy has a lower morbidity rate than surgery. The recently developed lumen-apposing metal stent can ease the drainage procedure, and has a higher technical and clinical success rate. Multidisciplinary management of WON infection is therefore the cornerstone of the management of this serious and sometimes fatal condition. Antibiotic therapy should be initiated when there is strong evidence of necrotic flow infection, in order to avoid selecting bacteria with a high level of resistance and fungal superinfections.